Type 1 diabetes is an autoimmune disease that leads to beta cell death. To test whether beta cell defects precede diagnosis, the expression of pCREB was surveyed in human islet cells. pCREB is a transcription factor produced by islet cells that regulates the expression of islet cell–specific genes. This analysis indicated that while islet cells of control donors displayed CREB/pCREB in the nucleus of alpha and beta cells, the transcription factor was also found in the cytoplasm of islet cells of normoglycemic GADA donors, donors with two antibodies and of those recently diagnosed. The translocation of CREB/pCREB, which decreases its activity, was correlated with reduced or absent expression of insulin and a protease. These changes suggest an alteration in protein homeostasis. The cytoplasmic localization of CREB/pCREB was transient, since the transcription factor moved to the nuclei of insulin cells of donors with longer standing disease. The fact that altered proteostasis leads to autoinflammation suggests that interventions at an initial stage of the disease, when protein homeostasis could be restored, may prevent the progress of the disease.
Campbell-ThompsonMFuAKaddisJSWasserfallCSchatzDAPuglieseAAtkinsonMA.Insulitis and beta-cell mass in the natural history of type 1 diabetes. Diabetes. 2016Mar;65(3):719–31.
2.
PuglieseA.Insulitis in the pathogenesis of type 1 diabetes. Pediatr Diabetes. 2016Jul;17(Suppl 22):31–6.
3.
AtkinsonMARoepBOPosgaiAWheelerDCSPeakmanM.The challenge of modulating beta-cell autoimmunity in type 1 diabetes. Lancet Diabetes Endocrinol. 2019Jan;7(1):52–64.
4.
MarreMLMcGintyJWChowITDeNicolaMEBeckNWKentSCPowersACBottinoRHarlanDMGreenbaumCJKwokWWPiganelliJDJamesEA.Modifying enzymes are elicited by ER stress, generating epitopes that are selectively recognized by CD4(+) T cells in patients with type 1 diabetes. Diabetes. 2018Jul;67(7):1356–68.
5.
RichardsonSJRodriguez-CalvoTGerlingICMathewsCEKaddisJSRussellMAZeisslerMLeetePKrogvoldLDahl-JørgensenKvon HerrathMPuglieseAAtkinsonMAMorganNG.Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. Diabetologia. 2016;59(11):2448–58.
6.
PinerosARKulkarniAGaoHOrrKSGlennLHuangFLiuYGannonMSyedFWuWAndersonCMEvans-MolinaCMcDuffieMNadlerJLMorrisMAMirmiraRGTerseySA.Proinflammatory signaling in islet beta cells propagates invasion of pathogenic immune cells in autoimmune diabetes. Cell Rep. 2022Jun28;39(13):111011.
7.
TeitelmanG.Abnormal expression of an insulin synthesizing enzyme in islets of adult autoantibody positive donors. J Histochem Cytochem. 2022;70(10):695–706.
8.
ApaolazaPSChenYCGrewalKLurzYBoulasselSVerchereCBRodriguez-CalvoT.Quantitative analysis of islet prohormone convertase 1/3 expression in human pancreas donors with diabetes. Diabetologia. 2024;67(12):2771–85.
9.
MeierDTRachidLWiedemannSJTraubSTrimigliozziKStawiskiMSauteurLWinterDVLe FollCBregereCGuzmanROdermattABoni-SchnetzlerMDonathMY.Prohormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing. Nat Commun. 2022Aug13;13(1):4761.
10.
MayrBMontminyM.Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol. 2001;2(8):599–609.
11.
AltarejosJYMontminyM.CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol. 2011;12(3):141–51.
12.
ChoISJungMKwonKSMoonEChoJHYoonKHKimJWLeeYDKimSSSuh-KimH.Deregulation of CREB signaling pathway induced by chronic hyperglycemia downregulates NeuroD transcription. PLoS ONE. 2012;7(4):e34860.
13.
BlanchetEVan de VeldeSMatsumuraSHaoELeLayJKaestnerKMontminyM.Feedback inhibition of CREB signaling promotes beta cell dysfunction in insulin resistance. Cell Rep. 2015Feb24;10(7):1149–57.
14.
Van de VeldeSWiaterETranMHwangYColePAMontminyM.CREB promotes beta cell gene expression by targeting its coactivators to tissue-specific enhancers. Mol Cell Biol. 2019Sep1;39(17):e00200–19.
15.
TeitelmanG.Human islets contain a beta cell type that expresses proinsulin but not the enzyme that converts the precursor to insulin. J Histochem Cytochem. 2020Oct;68(10):691–702.
16.
DybalaMPHaraM.Heterogeneity of the human pancreatic islet. Diabetes. 2019Jun;68(6):1230–9. doi:10.2337/db19-0072.
17.
DolibaNMRozoAVRomanJQinWTraumDGaoLLiuJManduchiELiuCGolsonMLVahediGNajiAMatschinskyFMAtkinsonMAPowersACBrissovaMKaestnerKHStoffersDAConsortiumH.α cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody-positive individuals. J Clin Invest. 2022Jun1;132(11):e156243.
18.
TalchaiCXuanSLinHVSusselLAcciliD.Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell. 2012Sep14;150(6):1223–34.
19.
Van OpdenboschNLamkanfiM. Caspases in cell death, inflammation, and disease. Immunity. 2019Jun18;50(6):1352–64.
20.
MeierJJBhushanAButlerAERizzaRAButlerPC.Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration?Diabetologia. 2005Nov;48(11):2221–8.
21.
TomitaT.Immunocytochemical localisation of caspase-3 in pancreatic islets from type 2 diabetic subjects. Pathology. 2010;42(5):432–7.
22.
TomitaT.Immunocytochemical localization of cleaved caspase-3 in pancreatic islets from type 1 diabetic subjects. Islets. 2010Jan–Feb;2(1):24–9.
23.
ErturkAWangYShengM.Local pruning of dendrites and spines by caspase-3-dependent and proteasome-limited mechanisms. J Neurosci. 2014Jan29;34(5):1672–88.
24.
OplandCKBryanMRHarrisBMcGillion-MooreJTianXChenYItanoMSDieringGHMeekerRBCohenTJ.Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity. iScience. 2023Jun16;26(6):106905.
25.
LounevaNCohenJWHanLYTalbotKWilsonRSBennettDATrojanowskiJQArnoldSE.Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer’s disease. Am J Pathol. 2008Nov;173(5):1488–95.
BurguillosMADeierborgTKavanaghEPerssonAHajjiNGarcia-QuintanillaACanoJBrundinPEnglundEVeneroJLJosephB.Caspase signalling controls microglia activation and neurotoxicity. Nature. 2011Apr21;472(7343):319–24.
28.
AcarinLVillapolSFaizMRohnTTCastellanoBGonzalezB.Caspase-3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation. Glia. 2007Jul;55(9):954–65. doi:10.1002/glia.20518.
29.
Rodríguez-BerrigueteGGalvisLFraileBde BethencourtFRMartínez-OnsurbePOlmedillaGPaniaguaRRoyuelaM. Immunoreactivity to caspase-3, caspase-7, caspase-8, and caspase-9 forms is frequently lost in human prostate tumors. Hum Pathol. 2012Feb;43(2):229–37.
30.
SabbaghLKaechSMBourbonniereMWooMCohenLYHaddadEKLabrecqueNAhmedRSekalyRP.The selective increase in caspase-3 expression in effector but not memory T cells allows susceptibility to apoptosis. J Immunol. 2004Nov1;173(9):5425–33.
GuoSDaiCGuoMTaylorBHarmonJSSanderMRobertsonRPPowersACSteinR.Inactivation of specific beta cell transcription factors in type 2 diabetes. J Clin Invest. 2013Aug;123(8):3305–16.
33.
WeitzJMenegazDCaicedoA.Deciphering the complex communication networks that orchestrate pancreatic islet function. Diabetes. 2021Jan;70(1):17–26.
34.
Rodriguez-DiazRTamayoAHaraMCaicedoA.The local paracrine actions of the pancreatic alpha-cell. Diabetes. 2020Apr;69(4):550–8.
35.
TeitelmanG.A controversy regarding the identity of the enzyme that mediates glucagon-like peptide 1 synthesis in human alpha cells. J Histochem Cytochem. 2024Aug–Sep;72(8–9):545–50.
36.
KedeesMHGrigoryanMGuzYTeitelmanG.Differential expression of glucagon and glucagon-like peptide 1 receptors in mouse pancreatic alpha and beta cells in two models of alpha cell hyperplasia. Mol Cell Endocrinol. 2009Nov13;311(1–2):69–76.
37.
ZhangYParajuliKRFavaGEGuptaRXuWNguyenLUZakariaAFFonsecaVAWangHMauvais-JarvisFSloopKWWuH.GLP-1 receptor in pancreatic alpha-cells regulates glucagon secretion in a glucose-dependent bidirectional manner. Diabetes. 2019Jan;68(1):34–44.
38.
CampbellSAGolecDPHubertMJohnsonJSalamonNBarrAMacDonaldPEPhilippaertKLightPE.Human islets contain a subpopulation of glucagon-like peptide-1 secreting alpha cells that is increased in type 2 diabetes. Mol Metab. 2020Sep;39:101014.
39.
SaikiaMHolterMMDonahueLRLeeISZhengQCWiseJLToderoJEPhuongDJGaribayDCochRSloopKWGarcia-OcanaADankoCGCummingsBP.GLP-1 receptor signaling increases PCSK1 and beta cell features in human alpha cells. JCI Insight. 2021;6:e141851.
40.
O’MalleyTJFavaGEZhangYFonsecaVAWuH.Progressive change of intra-islet GLP-1 production during diabetes development. Diabetes Metab Res Rev. 2014Nov;30(8):661–8.
41.
JhalaUSCanettieriGScreatonRAKulkarniRNKrajewskiSReedJWalkerJLinXWhiteMMontminyM.cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2. Genes Dev. 2003Jul1;17(13):1575–80.
42.
ShinSLe LayJEverettLJGuptaRRafiqKKaestnerKH.CREB mediates the insulinotropic and anti-apoptotic effects of GLP-1 signaling in adult mouse beta-cells. Mol Metab. 2014Nov;3(8):803–12.
43.
ChalovichEMZhuJHCaltagaroneJBowserRChuCT.Functional repression of cAMP response element in 6-hydroxydopamine-treated neuronal cells. J Biol Chem. 2006Jun30;281(26):17870–81.
44.
BitettoGDi FonzoA.Nucleo-cytoplasmic transport defects and protein aggregates in neurodegeneration. Transl Neurodegener. 2020Jul3;9(1):25.
45.
BorthwickGMJohnsonMAIncePGShawPJTurnbullDM.Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Ann Neurol. 1999Nov;46(5):787–90.
46.
LeeJKimCHSimonDKAminovaLRAndreyevAYKushnarevaYEMurphyANLonzeBEKimKSGintyDDFerranteRJRyuHRatanRR.Mitochondrial cyclic AMP response element-binding protein (CREB) mediates mitochondrial gene expression and neuronal survival. J Biol Chem. 2005Dec9;280(49):40398–401.
47.
AhmedBYHusnainOStaffordRHowardMGujarASMoradiyaVPatelKKSihotraS.Hyperphosphorylation of CREB in human dopaminergic neurons: a kinetic study of cellular distribution of total CREB and phospho-CREB following oxidative stress. Neuroreport. 2013Sep11;24(13):757–62.
48.
RobertsonRPHarmonJTranPOTanakaYTakahashiH.Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes. 2003Mar;52(3):581–7. doi:10.2337/diabetes.52.3.581.
49.
RaiMCurleyMColemanZDemontisF.Contribution of proteases to the hallmarks of aging and to age-related neurodegeneration. Aging Cell. 2022May;21(5):e13603.
50.
JayarajGGHippMSHartlFU.Functional modules of the proteostasis network. Cold Spring Harb Perspect Biol. 2020Jan2;12(1):a033951.
51.
OttensFFranzAHoppeT.Build-UPS and break-downs: metabolism impacts on proteostasis and aging. Cell Death Differ. 2021Feb;28(2):505–21.
52.
Baena-LopezLAWangLWendlerF.Cellular stress management by caspases. Curr Opin Cell Biol. 2024Feb;86:102314.
53.
SonninenTMGoldsteinsGLaham-KaramNKoistinahoJLehtonenS.Proteostasis disturbances and inflammation in neurodegenerative diseases. Cells. 2020Sep28;9(10):2183.
54.
ChenGYNuñezG.Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010Dec;10(12):826–37.
55.
KnebelUEPelegSDaiCCohen-FultheimRJonssonSPoznyakKIsraeliMZamashanskiLGlaserBLevanonEYPowersACKlochendlerADorY.Disrupted RNA editing in beta cells mimics early-stage type 1 diabetes. Cell Metab. 2024Jan2;36(1):48–61.
56.
PapendorfJJKrugerEEbsteinF.Proteostasis perturbations and their roles in causing sterile inflammation and autoinflammatory diseases. Cells. 2022Apr22;11(9):1422.
57.
CollierJJSparerTEKarlstadMDBurkeSJ.Pancreatic islet inflammation: an emerging role for chemokines. J Mol Endocrinol. 2017Jul;59(1):R33–46.
58.
ApaolazaPSBalcaceanDZapardiel-GonzaloJNelsonGLenchikNAkhbariPGerlingIRichardsonSJRodriguez-CalvoT nPOD-Virus Group. Islet expression of type I interferon response sensors is associated with immune infiltration and viral infection in type 1 diabetes. Sci Adv. 2021Feb;7(9):eabd6527.
59.
InselRADunneJLAtkinsonMAChiangJLDabeleaDGottliebPAGreenbaumCJHeroldKCKrischerJPLernmarkÅRatnerRERewersMJSchatzDASkylerJSSosenkoJMZieglerAG.Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care. 2015Oct;38(10):1964–74.
